Objective: A three-compartment kinetic model can predict the general progression of fatigue. This study aims to develop a three-compartment kinetic fatigue model for the isometric muscle endurance of the hip, knee, and ankle joints at 50% Isometric Peak Torque (IPT), offering a novel approach for simulation-based assessments and load evaluations in biomechanics and sports science. Methods: The IPT of the hip, knee, and ankle joints is measured in 40 male university students. Isometric endurance tests are then performed on all three joints at 50% IPT until exhaustion. Electromyography (EMG) data and endurance time (ET) of major lower limb muscles are collected concurrently. The differences between ETs predicted by models based on previously recommended F and R parameters and actual ETs are analyzed. Subsequently, experimental ETs are used in a grid search to optimize F and R parameters, allowing for the development of an accurate three-compartment kinetic model. Results: (1) The ET of the hip and ankle joints is significantly longer than that of the knee joint (p < 0.01). (2) Models using previously recommended F and R parameters overestimate ET, with significantly higher predicted values than experimentally measured ET (p < 0.01), as well as elevated RMSE and MRE values. (3) The grid search successfully identifies F and R parameters for the three-compartment model, with no statistical difference between model-predicted ET and experimental ET. Conclusion: The developed model can serve as an indirect measurement tool for evaluating load in similar activities.